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In a landmark decision for the field of cancer immunotherapy, the FDA has approved tisagenlecleucel, a personalized cellular therapy, developed by the University of Pennsylvania and Children's Hospital of Philadelphia (CHOP) for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

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"We're entering a new frontier in medical innovation with the ability to reprogram a patient's own cells to attack a deadly cancer," said FDA Commissioner Scott Gottlieb, MD. "New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses. At the FDA, we're committed to helping expedite the development and review of groundbreaking treatments that have the potential to be lifesaving."


"This is a turning point in the fight against B-cell ALL that opens up opportunities for patients across the world who desperately need new options," emphasized Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine at Penn's Perelman School of Medicine and Director of the Center for Cellular Immunotherapies at the Abramson Cancer Center.


"We're excited and proud to have moved this CAR therapy through all phases of development and clinical trials, established its efficacy, and now extended its reach to children across the country under this FDA approval," he added. "We hope the momentum behind the technology builds as we continue to investigate the abilities of personalized cellular therapeutics in blood cancers and solid tumors to help patients with many other types of cancer."


NCI estimates that approximately 3,100 patients ages 20 and younger are diagnosed with ALL each year. Tisagenlecleucel is approved for use in pediatric and young adult patients with B-cell ALL and is intended for patients whose cancer has not responded to or has returned after initial treatment, which occurs in an estimated 15-20 percent of patients.


"[Tisagenlecleucel] is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease," said Peter Marks, MD, PhD, Director of the FDA's Center for Biologics Evaluation and Research. "Not only does [tisagenlecleucel] provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials."


The safety and efficacy of tisagenlecleucel were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within 3 months of treatment was 83 percent.


Treatment with tisagenlecleucel has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS) and neurological events. Both CRS and neurological events can be life-threatening. Other severe side effects include serious infections, hypotension, acute kidney injury, fever, and hypoxia. Most symptoms appear within 1-22 days following infusion of tisagenlecleucel. Since the CD19 antigen is also present on normal B-cells, and tisagenlecleucel will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time.


Also, the FDA has expanded the approval of tocilizumab to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older. In clinical trials in patients treated with CAR-T cells, 69 percent of patients had complete resolution of CRS within 2 weeks following one or two doses of tocilizumab.


Because of the risk of CRS and neurological events, tisagenlecleucel is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense the treatment be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of tisagenlecleucel are required to be trained to recognize and manage CRS and neurological events.


Additionally, the certified health care settings are required to have protocols in place to ensure that tisagenlecleucel is only given to patients after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of CRS and neurological toxicities following infusion-and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with tisagenlecleucel.